Various therapeutic strategies in human beings are based on the use of therapeutic antibodies. This includes, for instance, the use of therapeutic antibodies developed to deplete target cells, particularly diseased cells such as virally-infected cells, tumor cells or other pathogenic cells. Such antibodies are typically monoclonal antibodies, of immunoglobulin gamma (IgG) species, typically with human IgG1 or IgG3 Fc portion. These antibodies can be native or recombinant antibodies, humanized mouse antibodies (i.e. comprising functional domains from various species, typically Fc portion of human or non-human primate origin, and variable region or complementary determining region (CDR) of mouse origin). Alternatively, the monoclonal antibody can be fully human through immunization in human Ig locus transgenic mice or obtained through cDNA libraries derived from human cells. A particular example of such therapeutic antibodies is rituximab (Mabthera®, Rituxan®), which is a chimeric anti-CD20 monoclonal antibody made with human γ1 and κ constant regions (therefore with human IgG1 Fc portion) linked to murine variable domains conferring CD20 specificity. In the past few years, rituximab has considerably modified the therapeutical strategy against B lymphoproliferative malignancies, particularly non-Hodgkin's lymphomas (NHL). Other examples of humanized IgG1 antibodies include alemtuzumab (Campath-1H®), which is used in the treatment of B cell malignancies or trastuzumab (Herceptin®), which is used in the treatment of breast cancer. Additional examples of therapeutic antibodies under development are disclosed in the art.
The mechanism of action of therapeutic antibodies developed to depletion of cells bearing the antigen specifically recognized by the antibody. This depletion can be mediated through at least four mechanisms: ADCC, complement dependent lysis, phagocytosis and direct antitumor effects, for example inhibition of tumor growth by mAb-mediated blockade of growth-receptor signalling.
While these antibodies represent a novel approach to human therapy, particularly in treatment of neoplasms, they do not always exhibit a strong efficacy. For instance, while rituximab, alone or in combination with chemotherapy was shown to be effective in the treatment of both low-intermediate and high-grade NHL, 30% to 50% of patients with low grade NHL have no clinical response to rituximab. It has been suggested that the level of CD20 expression on lymphoma cells, the presence of high tumor burden at the time of treatment or low serum rituximab concentrations may explain the lack of efficacy of rituximab in some patients. Nevertheless, the actual causes of treatment failure remain largely unknown. We have previously discovered that the tumor cell-killing efficacy of rituximab can be enhanced by boosting ADCC by natural killer (NK) cells. One mechanism by which NK cells can kill target cells is by ADCC, when a mAb binds with the antigen-specific portion to an antigen on a target cell, and at the same time the Fc portion of the mAb binds to an Fc-receptor (called CD16) on NK cells. This leads to activation of CD16 on the NK cell, which triggers activation of the NK cell cytolytic machinery. However, NK cells also express inhibitory receptors, such as KIR, which deliver negative signals to the NK cells, thereby balancing out positive signals for example transduced via CD16. We have found that by blocking the inhibitory KIR receptors, using mAb that bind to KIR and prevent its function, the stimulatory signalling through CD16 can be enhanced, leading to increased NK killing of tumor target cells, in the presence of mAbs that can simultaneously bind to an antigen on the target and to CD16 on NK cells.
WO2005003168 and WO2005003172 describe the use of cross-reactive anti-KIR antibodies for treating, e.g., cancer, an infectious disease or an immune disorder.
WO2005009465 describes the use of an antibody that blocks an NK cell inhibitory receptor and a therapeutic antibody that can be bound by CD16 to treat cancer, an infectious disease, or an immune disorder.
The present invention provides a method of enhancing the NK-mediated ADCC response towards virus-infected cells in the presence of therapeutic mAbs specific for antigens expressed on virally infected cells, as a treatment of viral infections, for example HIV-infections.